Sprayed synthetic pesticides have been used to control C. quatuordecimpunctata damage, but they pose problems because of residues and harm to natural enemies. Neither the microbial coleopteran-specific toxin from Bacillus thuringiensis tenebrionis, Cry3Aa, nor the fungal pathogen Beauveria bassiana have sufficient activity to effectively control C. quatuordecimpunctata SelleckIPI145 damage to asparagus. However, second instar C. quatuordecimpunctata

larvae exposed to a sublethal dose of Cry3Aa toxin demonstrated significantly higher larval mortality when exposed to B. bassiana. Our results suggest that a combination of Cry3Aa and B. bassiana may be effective in reducing damage by C. quatuordecimpunctata larvae AG-881 cost to asparagus. (C) 2011 Elsevier Inc. All rights reserved.”
“This paper presents a robust method to conduct inference in finely stratified familial studies under proband-based sampling. We assume that the interest is in both the marginal effects of subject-specific covariates on a binary response

and the familial aggregation of the response, as quantified by intrafamilial pairwise odds ratios. We adopt an estimating function for proband-based family studies originally developed by Zhao and others (1998) in the context of an unstratified design and treat the stratification effects as fixed nuisance parameters. Our method requires modeling only the first 2 joint moments of the observations and reduces by 2 orders of magnitude the bias induced by fitting the stratum-specific nuisance parameters. An analytical BAY 73-4506 concentration standard error estimator for the proposed estimator

is also provided. The proposed approach is applied to a matched case-control familial study of sleep apnea. A simulation study confirms the usefulness of the approach.”
“BACKGROUND Caffeic acid (CA) can inhibit toxin-induced liver injury. In this study, CA is assessed for its lipid lowering potential when oleic acid is used to induce non-alcoholic fatty liver disease in human HepG2 cells. RESULTS The results showed that both the triglyceride and cholesterol content are decreased in the HepG2 cells by using the enzymatic colorimetric method. CA enhances the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase. CA down-regulates the lipogenesis gene expression of sterol regulatory element-binding protein-1 and its target genes, fatty acid synthase in the presence of oleic acid. In addition, CA significantly decreases cholesterol and triglyceride production via inhibition the expression of both 3-hydroxy-3-methyglutary coenzyme A reductase and glycerol-3-phosphate acyltransferase. These effects are eliminated by pretreatment with compound C, an AMPK inhibitor. CONCLUSIONS These results demonstrate that CA inhibits oleic acid induced hepatic lipogenesis and the promotion of lipolysis via up-regulation of AMP-activated kinase.

We address the fundamental issue of how these cells work by applying a scanning electron microscopy-based technique to cell cross-sections. By mapping the variation Etomoxir mouse in efficiency of charge separation and collection

in the cross-sections, we show the presence of two prime high efficiency locations, one at/near the absorber/hole-blocking-layer, and the second at/near the absorber/electron-blocking-layer interfaces, with the former more pronounced. This ‘twin-peaks’ profile is characteristic of a p-i-n solar cell, with a layer of low-doped, high electronic quality semiconductor, between a p-and an n-layer. If the electron blocker is replaced by a gold contact, only a heterojunction at the absorber/hole-blocking interface remains.”
“Saturated fatty acids (SFA) have been reported to alter organelle integrity and function in many cell types, including

muscle and pancreatic beta-cells, adipocytes, hepatocytes and cardiomyocytes. SFA accumulation results in increased amounts of ceramides/sphingolipids and saturated phospholipids (PL). In this study, using a yeast-based model that recapitulates most of the trademarks of SFA-induced lipotoxicity in mammalian cells, we demonstrate that these lipid species act at different levels of the secretory pathway. Ceramides mostly appear to modulate the induction of the unfolded protein response and the transcription of nutrient transporters destined to the cell surface. On the other hand, saturated BB-94 PL, by altering membrane properties, directly impact vesicular budding at later steps in the secretory pathway, i.e. at the trans-Golgi Network level. They appear to do so by increasing lipid order within intracellular membranes which, in turn, alters the recruitment of loose lipid packing-sensing proteins, required for optimal budding, to nascent vesicles. We propose that this latter general mechanism could account for the well-documented deleterious impacts of fatty acids

find more on the last steps of the secretory pathway in several cell types.”
“It is widely accepted that the first photosynthetic eukaryotes arose from a single primary endosymbiosis of a cyanobacterium in a phagotrophic eukaryotic host, which led to the emergence of three major lineages: Chloroplastida (green algae and land plants), Rhodophyta, and Glaucophyta. For a long time, Glaucophyta have been thought to represent the earliest branch among them. However, recent massive phylogenomic analyses of nuclear genes have challenged this view, because most of them suggested a basal position of Rhodophyta, though with moderate statistical support. We have addressed this question by phylogenomic analysis of a large data set of 124 proteins transferred from the chloroplast to the nuclear genome of the three Archaeplastida lineages. In contrast to previous analyses, we found strong support for the basal emergence of the Chloroplastida and the sister-group relationship of Glaucophyta and Rhodophyta.

001). However, TH increased phase singularity number (wavebreaks) during VF (P<0.05) and Si pacing (P<0.05). TH resulted in earlier onset of APD alternans (P<0.001), which was predominantly SDA (P<0.05), and increased pacing-induced VF episodes (P<0.05). TH also decreased CV, shortened wavelength, and enhanced APD dispersion and the spatial heterogeneity of CV restitution.\n\nConclusions: TH (30 degrees C) increased the vulnerability of pacing-induced VF by (1) facilitating wavebreaks during VF and Si pacing, and (2) enhancing proarrhythmic electrophysiological parameters, including promoting

earlier onset of APD alternans (predominantly SDA) during Selleckchem Lazertinib S1 pacing. (Circ J 2009; 73: 2214-2222)”
“Brain metastasis has become an increasing cause of

morbidity PI3K inhibitor and mortality in cancer patients as the treatment of systemic disease has improved. Brain metastases frequently are highly vascularized, a process driven primarily by VEGF. VEGF mediates numerous changes within the vasculature including endothelial cell retraction and increased permeability, vasodilation, and new vessel formation. Here we describe a xenograft brain metastasis model that mimics the critical steps of metastasis including tumor cell dissemination and vascular adhesion, tumor growth and tumor associated angiogenesis. Magnetic resonance (MR) imaging was used to evaluate two aspects of the functional response of brain metastasis to the anti-VEGF receptor therapeutic, AZD2171 (Cediranib, RECENTIN (TM)). MR tracking of individual cells demonstrated that cediranib did not impede tumor

cell extravasation into the brain parenchyma despite evidence that anti-VEGF treatment decreases the permeability of the blood brain barrier. In a second assay, blood volume imaging using ultrasmall superparamagnetic iron oxide revealed that treatment of well-developed brain metastasis with cediranib for 7 days led to a heterogeneous response with respect to individual tumors. Overall, there was a significant average decrease in the tumor vascular bed volume. The majority of large tumors demonstrated substantially reduced central blood volumes relative to normal brain while retaining a rim of elevated blood volume at Selleck Buparlisib the tumor brain interface. Small tumors or occasional large tumors displayed a static response. Models and assays such as those described here will be important for designing mechanism-based approaches to the use of anti-angiogenesis therapies for the treatment of brain metastasis.”
“Objective: We describe the short-term results of the patients who underwent transapical treatment of a paravalvular leak (PVL) in our centre. Background: Increasing experience with transapical aortic valve implantation has inspired us to explore this approach for prosthetic paravalvular leak reduction in high risk patients.

\n\nMethods and Results: Rats were Sotrastaurin inhibitor injected with NaHS (an H2S donor, 2-200 mu mol.kg(-1).day(-1), i.p.) or saline for 3 weeks. MBP was measured with a tail-cuff method. C erebral arterioles were isolated and cannulated

in an organ bath system, and vessel diameters were measured with an image-shearing device. Changes in diameter in response to stepwise increases in intravascular pressure (20-120 mmHg) were investigated under no-flow conditions. After the treatments, plasma H2S increased and MBP decreased significantly. NaHS reduced the myogenic response in a dose-dependent manner. This effect was markedly attenuated by glibenclamide, a K-ATP channel blocker. Blockade of nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) enhanced,

whereas removal of the endothelium abolished the inhibitory role of NaHS on the myogenic response.\n\nConclusions: For the first time it has been demonstrated that H2S decreases the myogenic response of cerebral arterioles in vivo, and this effect is NF-��B inhibitor endothelium-dependent and partially mediated by K-ATP channels. (Circ J 2012; 76: 1012 1019)”
“BACKGROUND & AIMS: Liver X receptors (LXRs) are transcriptional regulators of cholesterol metabolism, controlling cholesterol flow into cells, catabolism, and efflux. Cholesterol controls cell proliferation; disruptions in cholesterol metabolism have been associated with the development of colon cancer. We investigated whether expression of activated LXR protects against intestinal tumorigenesis in mice. METHODS: We analyzed the development of colon cancer in mice that express a constitutive active form of LXR alpha only in the intestinal epithelium, under the control of villin promoter (iVP16LXR alpha). These mice were crossed with adenomatous polyposis coli (Apc)(min/+) mice,

or given azoxymethane followed by dextran sodium sulfate, to assess intestinal tumor formation. We also assessed proliferation and apoptosis of a human www.selleckchem.com/products/prt062607-p505-15-hcl.html colorectal cancer cell line (HT29) transfected with an adenoviral vector that expressed Ad VP16hLXR alpha, compared with cells expressing AdVP16 (control), and their ability to form xenograft tumors in mice. HT29 cells also were incubated with the LXR ligand GW3965. RESULTS: In human colorectal cancer cells, ligand-induced activation of LXR or transfection with Ad VP16hLXR alpha blocked the G1 phase, increased caspase-dependent apoptosis, and slowed growth of xenograft tumors in mice. iVP16LXR alpha mice formed fewer, smaller tumors than VP16 (control) mice after administration of azoxymethane and dextran sodium sulfate. APC(min/+)/iVP16LXR alpha mice also developed fewer, smaller intestinal tumors than APC(min/+)/iVP16 mice.

No gold standard for treating primary intradural MPNSTs has yet been established.\n\nPURPOSE: To report a rare case of primary intradural MPNSTs in a child AZD8055 supplier and review the literature pertaining to this rare disease.\n\nSTUDY DESIGN/SETTING: Case report and literature review.\n\nMETHODS: We report our experience with one new case. An 8-year-old boy diagnosed with primary intradural MPNSTs underwent three surgical excisions and two rounds of radiotherapy; however, metastasis to the brain was found, and the boy died 16 months after the first surgery. We also review the literature pertaining to both MPNSTs in general and primary intradural MPNSTs.\n\nRESULTS:

Surgery is currently the mainstay of MPNST treatment. Radiotherapy and chemotherapy are of limited value in these tumors. learn more Based on the review of the 24 cases described in the literature, including the present case, primary intradural MPNST is a very aggressive tumor with a very high recurrence rate even after gross total resection and with significant potential for leptomeningeal and systemic metastasis. The overall prognosis is very poor and seems to be worse than that of MPNSTs in general.\n\nCONCLUSIONS: Primary intradural MPNST is a very rare entity with

a poor prognosis. Surgical tumor removal combined with postoperative high-dose radiation may be recommended. Chemotherapy is usually reserved for patients with disseminated metastases or tumors that are unresectable at the time of diagnosis. (C) 2012 Elsevier Inc. All rights reserved.”
“Some sleep disorders are frequently found in the general population. The most common include restless legs syndrome, insomnia, and sleep apnea. These sleep disorders are well classified and can easily be diagnosed and treated. Since they are risk factors for cardiovascular and psychiatric disorders, early

diagnosis and treatment are essential to prevent these sequelae. The impairments caused by these sleep disorders (e.g., due to daytime sleepiness, sleep disruption, or cognitive Galardin datasheet deficits) can result in a significant reduction in a person’s quality of life. The diagnostic and therapeutic recommendations were taken from the S3 guideline “Nonrestorative sleep/sleep disorders” by the German Sleep Society. The levels of evidence were given according to the recommendations of the Oxford Centre for Evidence-based Medicine.”
“Background: cataract is a leading cause of reversible vision impairment and may increase falls in older adults. Objective: to assess the risk of an injury due to a fall among adults aged 60+, 2 years before first-eye cataract surgery, between first-eye surgery and second-eye surgery and 2 years after second-eye surgery. Design: a retrospective cohort study. Setting: Western Australian Hospital Morbidity Data System and the Western Australian Death Registry. Subjects: there were 28,396 individuals aged 60+ years who underwent bilateral cataract surgery in Western Australia between 2001 and 2008.

Four issues are examined from the perspective of econometrics. First, specification and Quizartinib validation of empirical models. Second, empirical issues associated with measures of advertising receptivity and exposure. Third, potential endogeneity of receptivity and exposure variables. Fourth, sample selection bias in baseline and follow-up surveys. Longitudinal studies reviewed include 20 studies of youth drinking and 26 studies of youth smoking. Substantial shortcomings are found in the studies, which preclude a causal interpretation.”
“Purpose:

Fitz-Hugh-Curtis Syndrome (FHCS) is a clinical entity characterized by inflammation of the liver capsule associated with genital tract infection. The aim of this study is to provide physicians with clinical suggestions for diagnostic approaches based on a. series of patients who were diagnosed with Nocodazole supplier FHCS. Materials and Methods: We conducted a retrospective study of patients who were diagnosed with FHCS after presenting to the emergency department (ED). The symptoms, physical examinations, laboratory findings, radiological findings, and progress of the patients were reviewed. Results: During the four-year study period, a total of 82 female patients received a final diagnosis of FHCS in the ED. Chlamydia

trachomatis was identified as a pathogen in 89% of the patients. Their clinical characteristics and laboratory findings were described. Fifty-two patients (63.4%) were admitted to the hospital. All of the admitted patients improved after treatment combining antibiotic therapy with conservative care. Conclusion: FHCS should be considered as a differential diagnosis for female patients of childbearing

age with right upper abdominal pain. Timely diagnosis using biphasic computed tomography (CT) with arterial and portal phases may help ensure adequate medical treatment as well as avoid invasive procedures.”
“Recent Vorinostat price stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients.

\n\nTwo hundred and sixty-two patients met inclusion criteria. VUR was detected in 21.3 %, urologic abnormality including VUR in 27.4 %. Degree of bladder distension, department of referring physician, study indication, positive documented urine culture, and history of recurrent UTI or UTI and other

LY3039478 research buy abnormality were all not associated with increased likelihood of VUR or any urologic abnormality on VCUG.\n\nVUR and VCUG abnormality are no more likely when performed after recurrent UTI or for UTI plus other abnormality. This reasons against postponing VCUG until after UTI recurrence, as positive findings are no more likely in this setting.”
“An atmospheric-pressure (AP) argon plasma discharge generated in a single-electrode configuration with the power supply operating at a frequency of 45 kHz is employed to perform some applications, such as the treatment of the interior surface of a medical infusion tube, hydrophilic modification of insulator surface, hardening of metal surface, and acidification treatment of water. It is shown that the active gases (O-2 and N-2) mixed in a carrier gas (Ar) play a significant role in carrying out such applications. A preliminary study on its applications is presented to demonstrate the promising potential BTSA1 in vitro of AP single-electrode-configuration plasma jet.”
“G-quadruplex-forming oligonucleotides

containing modified nucleotide chemistries have demonstrated promising pharmaceutical potential. In this work, we systematically investigate the effects of sugar-modified guanosines on the structure and stability of a (4+0) parallel and a (3+1) hybrid G-quadruplex using over 60 modified sequences containing a single-position substitution of 2′-O-4′-C-methylene-guanosine ((LNA)G), 2′-deoxy-2′-fluoro-riboguanosine ((F)G) or 2′-deoxy-2′-fluoro-arabinoguanosine ((FANA)G). Our results are summarized in two parts: (I) Generally, (LNA)G substitutions into Selleckchem CRT0066101 ‘anti’ position guanines within a guanine-tetrad

lead to a more stable G-quadruplex, while substitutions into ‘syn’ positions disrupt the native G-quadruplex conformation. However, some interesting exceptions to this trend are observed. We discover that a (LNA)G modification upstream of a short propeller loop hinders G-quadruplex formation. (II) A single substitution of either (F)G or (FANA)G into a ‘syn’ position is powerful enough to perturb the (3+1) G-quadruplex. Substitution of either (F)G or (FANA)G into any ‘anti’ position is well tolerated in the two G-quadruplex scaffolds. (FANA)G substitutions to ‘anti’ positions are better tolerated than their (F)G counterparts. In both scaffolds, (FANA)G substitutions to the central tetrad layer are observed to be the most stabilizing. The observations reported herein on the effects of (LNA)G, (F)G and (FANA)G modifications on G-quadruplex structure and stability will enable the future design of pharmaceutically relevant oligonucleotides.

Here, we show that stimulation of the thalamic input can reinforce a transient form of plasticity (E-LTP) induced by weak stimulation of the cortical inputs. This synaptic cooperation occurs within a time window of 30 min, suggesting that synaptic integration at amygdala synapses can occur within large time windows. Interestingly, we found that synaptic cooperation is not symmetrical. Reinforcement of a thalamic E-LTP by subsequent cortical stimulation is only observed within a shorter time window. We found that activation of endocannabinoid CB1 receptors is involved in the time

restriction of thalamic GM6001 purchase and cortical synaptic cooperation in an activity-dependent manner. Our results support the hypothesis that synaptic cooperation can underlie associative learning and that synaptic tagging and capture is a general mechanism in synaptic plasticity.”
“The GS-7977 chemical structure Fe(II)- and alpha-ketoglutarate (alpha KG)-dependent enzymes are a functionally and mechanistically diverse group of mononuclear nonheme-iron enzymes that activate dioxygen to couple the decarboxylation of alpha KG, which yields succinate and CO2, to the oxidation

of an aliphatic C-H bond of their substrates. Their mechanisms have been studied in detail by a combination of kinetic, spectroscopic, and computational methods. Two reaction intermediates have been trapped and characterized for several members of this enzyme family. The first intermediate is the C-H-cleaving Fe(IV)-oxo complex, which exhibits a large deuterium kinetic isotope effect on its decay. The second intermediate is a Fe(II):product complex. Reaction intermediates proposed to occur before the Fe(IV)-oxo intermediate do not accumulate and therefore cannot be characterized experimentally. One of these intermediates is the initial O-2 adduct, which is a FeO2(8) species in the notation introduced by Enemark and Feltham. Apoptosis Compound Library Here, we report spectroscopic and computational studies on the stable NO-adduct

of taurine:alpha KG dioxygenase (TauD), termed TauD-FeNO(7), and its one-electron reduced form, TauD FeNO(8). The latter is isoelectronic with the proposed O-2 adduct and was generated by low-temperature gamma-irradiation of TauD-FeNO(7). To our knowledge, TauD-FeNO(8) is the first paramagnetic FeNO(8) complex. The detailed analysis of experimental and computational results shows that TauD-(FeNO}(8) has a triplet ground state. This has mechanistic implications that are discussed in this Article. Annealing of the triplet FeNO(8) species presumably leads to an equally elusive FeHNO(8) complex with a quintet ground state.”
“Objective: To provide a critical overview of gene expression profiling methodology and discuss areas of future development.

, and Sanofi-Aventis. The authors have no other funding, financial relationships, or conflicts of interest to disclose.”
“Introduction: Inhaled hypertonic saline improves lung function and decreases pulmonary exacerbations in people with cystic fibrosis. However, side effects such as cough, narrowing of airways and saltiness cause intolerance of the therapy in 8% of patients.

The aim of our study was to compare the effect of an inhaled solution of hyaluronic acid and hypertonic saline with hypertonic solution alone on safety and tolerability. Methods: A total of 20 patients with cystic fibrosis aged 6 years and over received a single treatment regimen of 7% hypertonic saline solution or hypertonic solution with 0.1% hyaluronate for 2 days nonconsecutively after a washout period in an open crossover study.

Cough, throat irritation, JAK inhibitor and salty taste were evaluated by a modified ordinal score for assessing tolerability; “pleasantness” was evaluated by a five-level, Likert-type scale. Forced expiratory volume in 1 second was registered before and after the end of the saline inhalations. Results: All 20 patients (nine males, 11 females, mean age 13 years, range 8.9-17.7) completed the study. The inhaled solution of 0.1% hyaluronic MI-503 inhibitor acid and hypertonic saline significantly improved tolerability and pleasantness compared to hypertonic saline alone. No major adverse effects were observed. No difference was documented in pulmonary function tests between the two treatments. Conclusion: Hyaluronic acid combined with hypertonic saline solution may contribute to improved adherence to hypertonic saline therapy. Further clinical trials are needed to confirm our findings. Considering the extraordinary versatility of hyaluronic acid in biological reactions, perspective studies could define its applicability to halting progression of lung disease in cystic fibrosis.”
“Objective: To determine the rate of healthcare utilization for older primary care patients by depression status. Design: Cross-sectional data analysis. Setting: Primary care practices,

S3I-201 datasheet western New York state. Participants: 753 patients aged 65 years and older. Measures: Diagnostic depression categories were determined using the Structured Clinical Interview for DSM-IV (SCID). The Cornell Services Index (CSI) measured outpatient medical visits. Demographic, clinical, and functional variables were obtained from medical records and interview data. Results: 41.23% had subsyndromal or minor depression (M/SSD) and 53.15% had no depression. The unadjusted mean number of outpatient medical visits was greater in those with M/SSD (3.96 visits within 3 months) compared to those without depression (2.84), with a significant difference after adjusting for demographic, functional, and clinical factors. Conclusion: Those with M/SSD had higher rates of healthcare utilization compared with those without depressive symptoms.

“
“In this study, we attempted to improve the thermal rectification ratio (TRR = (J(AB) – J(BA))/J(BA)) of a thermal rectifier consisting find more of two Al-based

alloys, Al72.6Re17.4Si10 and Al71.6Mn17.4Si11, both of which are known to be the 1/1-cubic approximant of icosahedral quasicrystal. In order to estimate the thermal rectification ratio obtainable for a thermal rectifier made from two given materials, we employed a simple method of TRR calculation using the classical Fourier-law of heat conduction. The largest TRR, which exceeded 0.12 for the thermal reservoirs kept at T-H = 500 K and T-L = 300 K, was experimentally obtained, coinciding with what the calculations predicted. By using the experimentally determined thermal conductivity and the calculation method employed in this study, we show P5091 price the potential of an Al62Cu25.5Fe12.5 icosahedral quasicrystal as one of the constituent materials of

thermal rectifier possessing a TRR magnitude in excess of unity. (C) 2012 American Institute of Physics. [http://0-dx.doi.org.brum.beds.ac.uk/10.1063/1.4712420]“
“Vision is hampered in aging and diseases, such as age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and glaucoma. This review collates the fine structural alterations of the human retina in aging and various pathological situations and their links to the disease pathogenesis. It transpires that most changes occur at the level of the retinal pigment epithelium -Bruch’s membrane and the photoreceptor layer, causing visual problems to the sufferers. These changes include loss of normal, essential features of these cells and their gradual disappearance. It is important to understand in depth the selective vulnerability of this retinal region to alterations in aging and diseases. Evidence indicates that some of these changes may be mediated by the effects of oxidative stress, inflammation, and chronic light exposure. There

are changes also in the inner retinal layers, wherein hypertension, auto-immunity, hypoxia and ischemia could play significant roles in disease pathogenesis. Results of extensive research utilizing animal models have broadened our idea about photoreceptor pathology. However, Selleck Vadimezan equivalent knowledge on various changes in aging human retina and in dystrophies that affect the macula is not complete. Since cone photoreceptor and ganglion cell death are a potential problem, it is imperative to know about the basic facts on how they are affected and the mechanisms involved in their death. Thus, prevention of cone and ganglion cell loss should be the target of choice. This review also highlights the significant role played by electron microscopy in understanding such ultrastructural changes and future strategies utilizing it and other techniques to fill some of the existing lacunae and advance our knowledge. (c) 2012 Elsevier Ltd. All rights reserved.